PROJECT SUMMARY: ANALYTICAL CORE The proposed NIDA Center of Excellence, entitled Impact of Cannabinoids Across the Lifespan (ICAL), will test the hypothesis that non-physiological activation of the endocannabinoid (ECB) system in adolescence initiates a reprogramming of the genetic and epigenetic processes that govern this system?s molecular structure, neuroanatomical architecture, and synaptic functions, ultimately producing persistent abnormalities in cognition and motivated behavior. To test this hypothesis, ICAL will deploy a vertically integrated strategy combining molecular, neuroanatomical, electrophysiological, and behavioral approaches. The Analytical Core will utilize contemporary liquid chromatography/mass spectrometry (LC/MS) methods to achieve two specific aims: Aim 1: To provide analytical support to ICAL?s Animal Core. Working in close collaboration with the Animal Core, the Analytical Core will carry out drug metabolism and pharmacokinetics (DM-PK) studies to ensure that the THC treatment regimens employed by ICAL (a) produce consistent levels of systemic THC exposure across the various experimental groups under investigation (adolescent and adult mice and rats of both sexes); (b) are pharmacologically relevant (i.e., produce graded and defined degrees of CBR-dependent intoxication); and (c) take into consideration THC metabolism as well as accumulation in, and leakage from, lipid- rich tissues (e.g. white adipose). Aim 2: To provide bioanalytical support to ICAL projects. Even though ICAL?s Molecular, Synaptic and Behavioral Projects will advance in parallel, each will address specific questions that will require ECB quantification in brain tissue. The Analytical Core will fulfill this important experimental need. Its director, Dr. Faizy Ahmed, will have the following primary responsibilities: (a) implement LC/MS methods for the determination of THC and its metabolites in blood and other tissues; (b) implement LC/MS methods for the quantitative analysis of ECB lipids in the brain; (c) schedule shared use and maintenance of LC/MS instrumentation: (d) supervise a Senior Staff Research Associate (TBN; 25% effort) who will be responsible for sample preparation; and (e) train graduate students and post-doctoral scholars in the use of LC/MS equipment. In sum, working in collaboration with the Animal Core, the Analytical Core will generate a systematic set of robust pharmacodynamics and DM-PK data that will permit the development and implementation of pharmacologically and translationally relevant THC treatment protocols.